JAK inhibition increases bone mass in steady-state conditions and ameliorates pathological bone loss by stimulating osteoblast function.

Science translational medicine 2020 Feb 12

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Janus kinase (JAK)-mediated cytokine signaling has emerged as an important therapeutic target for the treatment of inflammatory diseases such as rheumatoid arthritis (RA). Accordingly, JAK inhibitors compose a new class of drugs, among which tofacitinib and baricitinib have been approved for the treatment of RA. Periarticular bone erosions contribute considerably to the pathogenesis of RA. However, although the immunomodulatory aspect of JAK inhibition (JAKi) is well defined, the current knowledge of how JAKi influences bone homeostasis is limited. Here, we assessed the effects of the JAK inhibitors tofacitinib and baricitinib on bone phenotype (i) in mice during steady-state conditions or in mice with bone loss induced by (ii) estrogen-deficiency (ovariectomy) or (iii) inflammation (arthritis) to evaluate whether effects of JAKi on bone metabolism require noninflammatory/inflammatory challenge. In all three models, JAKi increased bone mass, consistent with reducing the ratio of receptor activator of NF-κB ligand/osteoprotegerin in serum. In vitro, effects of tofacitinib and baricitinib on osteoclast and osteoblast differentiation were analyzed. JAKi significantly increased osteoblast function (P < 0.05) but showed no direct effects on osteoclasts. Additionally, mRNA sequencing and ingenuity pathway analyses were performed in osteoblasts exposed to JAKi and revealed robust up-regulation of markers for osteoblast function, such as osteocalcin and Wnt signaling. The anabolic effect of JAKi was illustrated by the stabilization of β-catenin. In humans with RA, JAKi induced bone-anabolic effects as evidenced by repair of arthritic bone erosions. Results support that JAKi is a potent therapeutic tool for increasing osteoblast function and bone formation. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Citation

Susanne Adam, Nils Simon, Ulrike Steffen, Fabian T Andes, Carina Scholtysek, Dorothea I H Müller, Daniela Weidner, Darja Andreev, Arnd Kleyer, Stephan Culemann, Madelaine Hahn, Georg Schett, Gerhard Krönke, Silke Frey, Axel J Hueber. JAK inhibition increases bone mass in steady-state conditions and ameliorates pathological bone loss by stimulating osteoblast function. Science translational medicine. 2020 Feb 12;12(530)